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Relationship Between Calcium and Phosphate

There is a chemical equilibrium between calcium and phosphate. Thus, calcium homeostasis cannot be considered without understanding the relationship between calcium and phosphate.

  1. Bone is a complex precipitate of calcium and phosphate called hydroxyapatite, which is laid down in a protein (osteoid) matrix. Bone formation or resorption depends on the prod­uct of their concentrations called solubility product.

[Ca2+] X [PO4] > solubility product = bone deposition

 [Ca2+] X [PO4] < solubility product = bone resorption
 

Thus, a decrease in the interstitial concentration of either Ca2+ or phosphate promotes the resorption of these salts from bone (demineralization). It is the free Ca2+, not the phosphate, that is regulated so precisely. Hormonal control of free Ca2+ levels is almost entirely achieved via parathyroid 

  1. Bone Cells
    1. Osteoblasts: (bone forming) arise from osteoprogenitor cells of mesenchymal origin.
    2. Osteocytes: Osteoblasts become entrapped in mineralized bone differentiate into osteocytes.
    3. Osteoclasts (resorb bone) arise from monocytes that migrate to bone. Several monocytes fuse to form the multinucleated osteoclasts.
  2. Parathyroid Hormone (PTH)

PTH is a peptide hormone released from the parathyroids in response to lowered interstitial free Ca2+.

The function of PTH is to raise free Ca2+, which it does by several mechanisms. 

  1. Actions of Parathyroid Hormone
    1. Receptor on Osteoblasts not Osteoclasts.
    2. PTH increases Ca2+ reabsorption in the distal tubule of the kidney and decreases phosphate reabsorption in the proximal tubule.
    3. By decreasing renal phosphate reabsorption, PTH lowers plasma phosphate. This causes the product of the Ca2+ and phosphate concentrations to be less than the solubility product. This, in turn, promotes the resorption of these ions from bone and raises their concentration in the circulating blood.
    4. PTH slowly increases the formation and activity of osteoclasts indirectly, which resorb bone, releasing Ca2+ via RANK receptors. These receptors are activated by RANK ligand present on osteoblasts which is induced by PTH.
    5. PTH increases the formation of 1,25 di-OH (active vitamin D) in the proximal tubules of the kidney, which leads to increased absorption of Ca2+ and phosphate from the small intestine.
  2. Calcitonin    

Calcitonin (CT) is a peptide hormone secreted by the parafollicular cells (C cells) of the thyroid gland. It is released in response to elevated free calcium. Calcitonin lowers plasma calcium by decreasing the activity of osteoclasts, thus decreasing bone resorption. Its receptor is on Osteoclasts.

 

F. VITAMIN D3 (CHOLECALCIFEROL)
 

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  1. The synthesis of 1,25 di-OH D3 occurs sequentially in the skin —> liver -» kidney.
  2.  After its conversion to the 25 OH form in the liver, it can be stored in fat tissue. The serum levels of 25 OH vitamin D represent the best measure of the body stores of vitamin D when.
  3. Most of the 25 OH form, which is the immediate precursor of 1,25 di-OH D3 is converted to the inactive metabolite, 24,25 di-OH D3
  4. The normal plasma level of 25-hydroxycholecalciferol is about 30 ng/mL, and that of 1,25-dihydroxycholecalciferol is about 0.03 ng/mL (approximately 100 pmol/L).

G. Actions of 1,25 di-OH D3

  1. Under normal conditions, vitamin D acts to raise plasma Ca2+ and phosphate. Thus, vitamin D.
  2. promotes bone deposition. This is accomplished by:
  • 1,25 di-OH D3 increases the absorption of Ca2+ and phosphate by the intestinal mucosa by increasing the production of Ca2+-binding proteins(Calbindin).
  • The resulting high concentrations of Ca2+ and phosphate in the extracellular fluid exceed the solubility product, and precipitation of bone salts into bone matrix occurs.
  • 1,25 di-OH D3  increases the reabsorption of Ca2+ by renal distal tubule.
  1. Receptors for 1,25 di-OH D are on the nuclear membranes of osteoblasts.
Example

Which of the following is not true regarding Vitamin D? (AIIMS May 08)

  1. 1 hydroxylation occurs in kidney.
  2. 25-hydroxylation takes place in the liver.
  3. In absence of sunlight 200-400 IU of vitamin D is the daily required.
  4. William’s syndrome is characterized by precocious puberty, obesity and mental retardation.
Solution

3. In absence of sunlight 200-400 IU of vitamin D is the daily required.

   

Other Hormones

  1. Glucocorticoids lower plasma Ca2+ levels by inhibiting osteoclast formation and activity, but over long
  2. periods they cause osteoporosis by decreasing bone formation and increasing bone resorption.
  3. Growth hormone increases calcium excretion in the urine, but also increases intestinal absorption of Ca2+,   
  4. resultant action is positive calcium balance.
  5. Insulin-like growth factor I (IGF-I) stimulates protein synthesis in bone.
  6. Thyroid hormones cause hypercalcemia, hypercalciuria and osteoporosis.
  7. Estrogens prevent osteoporosis by inhibiting the stimulatory effects of certain cytokines on osteoclasts.
  8. Insulin increases bone formation, and there is significant bone loss in untreated diabetes.

Summary:
 

 

Ca++

PO43-

 

1,25 DHCC

Calcitonin

PTH

 

Disorder of parathyroid

PTH

Serum Calcium

Serum PO4

Primary Hypo

Decreased

Decreased

Increased

Pseudo Hypo

Increased

Decreased

Increased

Pseudo-pseudo Hypo

Normal

Normal

Normal

Secondary Hypo

Decreased

Increased

Increased

Primary Hyper

Increased

Increased

Decreased

Pseudo Hyper

PTH-rP increased

Increased

Decreased

Secondary Hyper (Due to chronic renal failure)

Increased

Decreased

Increased (due to decreased GFR)

Secondary Hyper (due to other causes)

Increased

Decreased

Decreased

Tertiary

Initially like secondary, later like primary





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